Mineral compositions are commonly taken as dietary aids, either as therapeutic preparations directed to a specific medical problem or as general nutritional supplements. Among useful dietary supplements are dosage units of calcium citrate, orally administered in solid or liquid form (U.S. Pat. Nos. 4,772,467, 4,814,177, and 4,851,221; each patent herein incorporated by reference). Oral administration of calcium citrate as a nutritional supplement both modestly increases levels of urinary citrate and provides bioavailable calcium. By modestly increasing levels of urinary citrate, administration of calcium citrate counters calcium nephrolithiasis (i.e., formation of calcium-containing kidney stones). Furthermore, calcium is more readily absorbed when administered as calcium citrate than as calcium carbonate, i.e., the administration of calcium citrate provides calcium that is more bioavailable. Improved absorption of calcium allows more effective treatment of calcium-deficiency conditions like osteoporosis.
In U.S. Pat. No. 6,287,607, Pak et al., espoused a single compound with discrete empirical formula of potassium calcium citrate in a tablet formulation, that enjoyed bulk density of 0.8-1.3 g/cc and molar ratio of 1:1:1 or 4:1:2. The '607 patent also taught that a tablet formulation would counter kidney stone formation and bone loss based on single dose bioavailability studies.
Potassium citrate is widely used for the prevention of kidney stone formation. It has been shown to be effective in increasing urinary citrate, which is well known to retard the formation of calcium-containing kidney stones. Thus, this citrate salt of potassium has regulatory approval for the prevention of kidney stones containing calcium oxalate, the most common constituent of stones (Pak et al., 1985, J. Urol. 134:11-19). Potassium citrate is also an effective alkalinizing agent (Sakhaee et al., 1991, J. Clin. Endo. Metab. 72:396-400). By increasing the pH of urine, this treatment also prevents uric acid stones that have a tendency to form in relatively acidic urine.
There is emerging evidence that alkali delivered into the body by potassium citrate may protect against bone loss. Potassium citrate treatment has been shown to prevent calcium loss into urine (Sakhaee et al., 1991, J. Clin. Endo. Metab. 72:396-400) and to increase bone density (Pak et al., 2001, J. Urol. 168:31-34). A typical dose of potassium citrate is 20 mEq (20 mmol) twice daily.
Calcium supplementation is also widely recognized to be a linchpin for countering bone loss that occurs following menopause. It works by increasing the level of calcium in the blood by providing sufficient calcium to be absorbed from the bowel. This rise in blood calcium then suppresses the secretion of parathyroid hormone that cause bone destruction, preventing bone loss. Calcium citrate and calcium carbonate are two widely used calcium supplements for this purpose. Calcium citrate is believed to be preferable, because it is generally better absorbed (Heller et al., 2000, J. Clin. Pharmacol 40:1237-1244). Moreover, calcium citrate supplementation modestly increases urinary citrate, an inhibitor of kidney stone formation; thus, the risk of stone formation that might rise from calcium supplementation is thought to be low from this supplementation. Some patients with calcium oxalate stones have high urinary oxalate from absorbing too much oxalate from the bowel. Calcium citrate may be helpful by binding oxalate and preventing its absorption. A typical dose of calcium citrate for the prevention of bone loss is 400-500 mg calcium given twice daily (Ruml et al., 1999, Am. J. Therap. 6:303-331).
While prior art teaches the use of calcium supplementation, it does not do so for a powder formulation of potassium calcium citrate as mixtures of pure chemical salts having efficacy for the treatment and prevention of kidney stones and osteoporosis. In U.S. Pat. No. 6,680,305, a single compound with unique formula as a tablet formulation was disclosed. The compound had a molar ratio of 1:1:1 for potassium, calcium and citrate. Another compound had a molar ratio of 4:1:2. As discrete entities, they had a bulk density of 0.8 to 1.3 g/cc. The invention disclosed herein relates to a modification of potassium calcium citrate that is an improvement of tablet formulations of U.S. Pat. No. 6,680,305.
In U.S. Pat. Nos. 6,319,490; 6,719,963; and 6,908,909, liquid oral compositions comprising a calcium compound and an acidulant are disclosed. The '490, '963, and '909 patents deal with adding calcium salt to acidic beverage to prevent erosion of teeth. The product contains no potassium, an essential ingredient to achieve the benefits of the present invention. The pH range disclosed in the patents is 3.5-4.5, whereas that of the present invention is higher; ˜4.5 to ˜6. Thus, unlike the present invention, the teachings of this patent family do not provide an alkali load to the extent that the composition of the present invention does so.
U.S. Pat. No. 6,680,305 teaches physiologically acceptable aqueous solutions and methods for their use. The '305 patent deals with making a parenteral solution that has electrolytes and buffer into which drugs to fight cancer and nutrients (hydroxyethyl starch) can be added. In contrast, the present invention is orally administered.
In U.S. Patent Application Publication No. 2004/0185119, methods and compositions are disclosed for treating gastric hyperacidity while diminishing the likelihood of producing vitamin deficiency. This patent deals with oral preparation of antacid or drugs which inhibit gastric acid secretion. The objective is to reduce gastric acidity without interfering with absorption of vitamins. No particular ratio of K:Ca:citrate is discussed.
U.S. Pat. Nos. 4,871,554 and 4,722,847 disclose methods of adding calcium salt to citrus-containing fruit juices for calcium fortification of juices. An important ingredient in one patent is malic acid, and that in another is phosphate. The patents mention calcium bioavailability, but nothing of alkali load, rise in urinary citrate or stone prevention, which are the focus of our patent. No importance to the K:Ca:citrate ratio is made.
In the present disclosure, the evidence from a carefully conducted metabolic study in human beings is offered, revealing that the combination of commonly used doses of potassium citrate (20 mEq twice day) and calcium citrate (400 mg calcium twice daily), which deliver potassium and calcium at a molar ratio of 2:1, is better than calcium citrate in averting bone loss, and is better than potassium citrate in preventing kidney stone formation.